Having personally encountered mental illness in his own family, Bryan L. Roth, M.D., Ph.D., member of the Brain & Behavior Research Foundation Scientific Council, has worked throughout his career to find better treatments for people living with brain and behavior disorders.

“From a very young age, I’ve been exposed to the devastation caused by serious mental illness,” Dr. Roth says. “When I was a child, I had a close family member who had schizophrenia. I also had a close relative who took her own life because of recurrent bipolar disorder.”

This deeply sensitized Dr. Roth, a reaction perhaps even more pronounced as a consequence of geography. “I’m from a town in Montana so small it didn’t even have a psychiatrist. My relative with schizophrenia had to be sent away, for a long period, to the Warm Springs State Hospital, which was some distance from where we lived. That had a huge effect on me.”

Dr. Roth’s motivating family experiences coincided with his natural gifts in biology and chemistry, which became evident in his early school years. From his first exposure in college to how nerve cells in the brain communicate, he became convinced “that this is where the important answers to mental illness would eventually come from.” He earned M.D. and Ph.D. degrees at St. Louis University Medical School, and after postdoctoral research at the NIMH, Dr. Roth went on to a psychiatric residency at Stanford University Medical Center. His mentor there, Dr. Roland Ciranello, was an early member of the Brain & Behavior Research Foundation (then NARSAD) Scientific Council, as was the researcher who recruited him for his first academic appointment at Case Western Reserve University: Dr. Herbert Meltzer, a pioneer in the development of the second generation, or ‘atypical,’ antipsychotic medications.

NARSAD Grants were critical support
These mentoring relationships of Dr. Roth’s reflect the way the Brain & Behavior Research Foundation has shaped the development of the mental health research field. From its earliest days, it has supported scientists that have come to be the leaders in psychiatry and neuroscience and who have, in turn, served on the organization’s Scientific Council. The Scientific Council reviews all grant applications, selecting the most promising ideas and eventually mentoring the chosen grantees.

Dr. Meltzer not only recruited Dr. Roth, but urged him to apply for a NARSAD Young Investigator Grant. It was great advice, Dr. Roth says, for at the time around 1991 “I was just starting out in my own lab at Case Western, and grants were very hard to come by, even more so than today. The government was rejecting 95 out of every 100 grant applications, which meant a lot of worthy science was not being funded.”

Without the Brain & Behavior Research Foundation “there was no way my early work could have gotten off the ground. And that’s the whole purpose of NARSAD Grants,” Dr. Roth says. “They gave me resources when I didn’t have any.” In fact, Dr. Roth says, the work supported by that first grant yielded a number of “my most highly cited scientific papers, which still hold up pretty well today, I’m pleased to say.” These papers are about the way atypical antipsychotic drugs such as clozapine produce their effects, a subject that continues to be important not only for Dr. Roth but for the entire psychiatric community.

Discoveries about a drug’s mechanism of action are vital. Knowing exactly how a drug affects the biology and chemistry of the body, and particularly the part of the body where it generates its therapeutic effects, is crucial.

Dr. Roth and colleagues have learned that clozapine interacts with at least 73 different protein ‘targets’ in the brain. The development of the science that makes possible tracking and identifying all of these targets is itself an important achievement. Beyond this, the discovery of clozapine’s many interactions raises all sorts of questions, which have provided new points of departure for Drs. Roth, Meltzer and many others.

The nub of the issue is this: if a drug affects 73 different targets, then which of these account for the benefits it brings patients? Which targets are specifically associated with which positive effects? Which targets in particular can be associated with specific side effects?

Adding another layer of complexity: How do the answers to the above questions vary in different patients? Can they explain why certain patients are helped more by a given drug than other patients? Why some derive little or no benefit? Why some suffer certain side effects and others don’t?

All of these hard to answer questions might reduce to this ultimate one: How do scientists develop psychiatric drugs that work better for more patients, with an absolute minimum of side effects?

‘Silver bullets’ vs. ‘magic shotguns’
The discoveries that have come out of Dr. Roth’s lab over two decades (see sidebar) call attention to a major debate that has deeply influenced many teams of drug developers. Using clozapine as a case in point, Dr. Roth explains: “An idea arose, when we discovered in the ’90s how many different targets the drug hits, that one of those targets was going to be the key that accounts for the drug’s positive effects” and that if it could be isolated, the drug could be reengineered to hit just that target and no others, thus minimizing side effects.

The idea of such a drug a ‘silver bullet’ “seemed reasonable at the time,” Dr. Roth says. “But in retrospect, it has proved naïve. We now know that illnesses like schizophrenia are so much more complex than we ever imagined.” The game changer was the Human Genome Project and the remarkable technologies it has spawned, which have made possible the discovery of potentially hundreds of genetic causes of complex illnesses like schizophrenia.

The pharmaceutical industry spent a great deal of time and money searching in vain for psychiatric silver bullets. But this is how scientific knowledge is gained experiments are conducted, the outcome of which can’t be known in advance. Dr. Roth accentuates the positive implications: while the idea of single target therapies did not pan out in the area of psychiatric medications partly reflecting the complexity of the brain it has proven a valuable approach in cancer drug development. But even in psychiatry, the data have clearly identified many targets that do account for serious side effects, and these have indicated various ways to make existing drugs more tolerable for more patients.

Just as important, the data on multiple targets points to what effective psychiatric drugs do in the brain. It’s probable, Dr. Roth says, that drugs like clozapine derive much of their therapeutic benefit precisely because they hit multiple targets. He calls the lesson from this the “magic shotgun” approach to drug development, referring to a shotgun’s propensity to ‘spray’ its fire over a wider area than a single bullet. “We can certainly develop highly selective drugs,” he says, “and we’ll find subsets of patients who will respond to these, but that population is likely to be small in each case.”

How, then, to go forward? Dr. Roth believes the magic shotguns could provide the greatest benefit for the greatest number of psychiatric patients due to the complexity of brain chemistry. The specific hope, in schizophrenia, “is that genetic data will reveal neural circuits involved in the illness, and that we will learn how to modulate these neurocircuits with drugs. The idea is that we can test ideas we have about which neural circuits are important for various diseases. That’s where technologies have really opened new doors” (see sidebar).

No one has to tell Bryan Roth about the urgency of finding better drugs. “My relative with schizophrenia lived as a street person on and off for 25 years, refusing to take medicine because of the debilitating side effects,” he says. “When we finally got her on one of the newer ‘atypical’ medications, it absolutely transformed her life.” Poignantly, she invariably asks him, in their frequent phone chats, “Have you learned anything new about schizophrenia today, Bryan?”

With the continued investment from the Brain & Behavior Research Foundation in innovative ideas and promising scientists, Dr. Roth is confident that he and other scientists will continue to answer, “Yes.”

Bryan L. Roth, M.D., Ph.D.
Scientific Council Member
Michael Hooker Distinguished Professor
Department of Pharmacology, School of Medicine
Department of Medicinal Chemistry and Natural Products, School of Pharmacy
Director, NIMH Psychoactive Drug Screening Program
University of North Carolina Chapel Hill Medical School